: This proposal examines malaria transmission and biology, beginning with the mosquito vector continuing with human and clinical outcomes and culminating in an examination of the mechanisms responsible for genetic diversity. In Project 1 the question being asked is the nature of the process that drives differentiation of malaria parasites in the human bloodstream to the sexual forms responsible for transmission. This Project is strengthened by a comprehensive array of field studies, which are complimented by molecular expertise in gene expression using microarrays to identify genes potentially essential in this process. The second Project provides a transition from mosquitoes to humans by measuring human exposure to infectious bites, and examines two important unsolved problems: malaria in pregnancy and the semi-immune state. By following women during pregnancy and their newborn children after birth, this Project should determine the risk of congenital infection among children whose mothers were frequently infected during pregnancy, and whether maternal infection produces a form of tolerance in the child that reduces the risk of severe disease in early childhood. Significant basic issues in these studies include the potential importance of neutralizing antibodies for GPI, as well as antibodies to more traditional antigens and cellular responses to the parasite. The third Project examines genetic diversity in the parasite and the mechanisms responsible for that diversity. Mechanisms that will be explored in detail include homologous recombination, spontaneous point mutation and spontaneous deletions. Based on studies performed during the past several years it is likely that homologous recombination during meiosis may be the most important factor in this process. From a basic science perspective, these studies bring modern technology such as real time PCR, DNA microarrays, and modern carbohydrate chemistry to bear upon malaria. From a public health perspective, understanding the basis of transmission, of malaria in pregnancy of the semi-immune state and genetic diversity should substantially increase the opportunities for malaria control.